[0001] This invention relates to a novel process for the production of N-acetyl-para-aminophenol
(APAP) by the Beckmann rearrangement of 4-hydroxyacetophenone oxime using an acid
catalyst. The invention is also concerned with an integrated process for preparing
APAP by first producing 4-hydroxyacetophenone oxime from 4-hydroxyacetophenone (4-HAP),
extracting the oxime from the reaction mixture with a solvent, and proceeding with
the acid catalyzed Beckmann rearrangement of 4-hydroxyacetophenone oxime in the solvent
used to extract the oxime.
BACKGROUND OF THE INVENTION
[0002] It is known to prepare N-acyl-hydroxyaromatic amines, e.g., N-acetyl-para-aminophenol
(APAP), by acetylating the corresponding hydroxy aromatic amine, e.g. para-aminophenol,
with an acetylating agent such as an anhydride, e.g., acetic anhydride. However,this
reaction may cause problems such as the difficulty of mono-acetylating the amine group,
oligomerization of the hydroxy aromatic amine, and color body formation. Nonetheless,
the APAP made by this reaction is an important commodity of commerce, being one of
the most widely used over-the-counter analgesics.
[0003] In U.S. 4,524,217 there is disclosed a novel process for the preparation of N-acyl-hydroxy
aromatic amines, in general, and N-acetyl-para-aminophenol (APAP), in particular.
The APAP is formed by a two-step process in which the first step involves reacting
4-hydroxyacetophenone (4-HAP) with a hydroxylamine salt and a base to obtain the ketoxime
of the ketone (4-HAP oxime), and then subjecting the ketoxime to a Beckmann rearrangement
in the presence of a catalyst to form APAP. Although various materials can be used
as the Beckmann rearrangement catalyst, U.S. 4,524,217 discloses preferred use of
thionyl chloride in liquid sulfur dioxide. The entire content of U.S. 4,524,217 is
herein incorporated by reference.
[0004] Although sulfur dioxide has been found to be an excellent solvent for the Beckmann
rearrangement of 4-HAP oxime to APAP or acetaminophen, there are certain characteristics
of sulfur dioxide which are disadvantageous. For one, SO₂ is toxic. Accordingly, extraordinary
precautions must be taken to handle and contain the sulfur dioxide and such precautions
obviously require specialized equipment and procedures. For example, centrifuges do
not adequately contain sulfur dioxide and therefore cannot be used for separation
of the crude solid APAP product from the sulfur dioxide reaction liquor. Consequently,
such separation must be accomplished by filtration with equipment that is more expensive
to purchase and operate than a centrifuge. Furthermore, centrifugation is inherently
suited for continuous processing, whereas filtration is not. Additionally, SO₂ is
corrosive and requires expensive metallurgy. Use of SO₂ as solvent may also lead to
the formation of metallic contaminants from the processing equipment. Such contaminants
may affect reaction rates and/or lead to the formation of by-products. Obviously,
since APAP is an analgesic for human consumption, the product should be as pure as
possible, and, thus, minute impurities from corrosion products are definitely not
desirable. Removal of corrosion products from the APAP adds to the operating costs.
Moreover, the SO₂ must be pressurized for use in the liquid state as solvent. Pressurization,
containment, and corrosion problems all require additional equipment and operating
costs.
[0005] Another disadvantage with the prior two-step process of producing APAP from 4-HAP
by first forming the 4-HAP oxime and then subjecting the oxime to Beckmann rearrangement
with thionyl chloride in SO₂ is that the oxime is prepared in water and must be recovered
by chilling the aqueous oximation product to crystallize the oxime. The crystallized
oxime must then be collected from the aqueous oximation liquor, washed, and dried
prior to Beckmann rearrangement. The dried oxime is then fed to the APAP reactor via
a hopper system. This arrangement requires solids crystallization, collection, drying,
storage, and handling and the consequent use of additional and expensive equipment.
[0006] Use of sulfur dioxide as the solvent for Beckmann rearrangement has yet further disadvantages.
Before the crude APAP product can be neutralized and purified in aqueous media, substantially
all of the sulfur dioxide solvent must be removed. Such removal requires filtration
of sulfur dioxide from the crude solid APAP product, evaporation of most sulfur dioxide
remaining on the crude solid APAP filter cake, and, finally, chemical neutralization
of any sulfur dioxide still remaining on the crude solid APAP. Recovery of the sulfur
dioxide evaporated or neutralized from the crude solid APAP is difficult and sometimes
uneconomical. During subsequent purification, the crude solid APAP is dissolved off
the filter with hot water. Substantially all traces of water must then be removed
from the filter and its containment vessel before entry of the sulfur dioxide/APAP
product slurry from the next batch. Sulfur dioxide recovered from the Beckmann reaction
must remain substantially anhydrous to be suitable for use in subsequent Beckmann
reactions. Removal of water from sulfur dioxide is difficult and/or impractical. The
additional equipment and procedures needed to remove sulfur dioxide from the crude
solid APAP product and to then remove water from the filter and its containment vessel
add to both capital and operating costs.
[0007] Accordingly, it would be advantageous to provide an alternative solvent to SO₂ for
use in the Beckmann rearrangement of 4-HAP oxime to APAP. Such a solvent should be
less toxic, less volatile, and less corrosive than SO₂. The solvent must also provide
good yields of APAP, preferably at least about 50% and more preferably at least about
60%. The solvent must also provide for the formation of a pure APAP product having
a melting point range preferably between about 168° C and about 172° C (the USP specification)
and having a dry-basis purity of preferably at least about 98% wt % (the USP specification)
and more preferably at least about 99.9 wt %. As disclosed in copending aforementioned
U.S. Serial No. 217,652, ester solvents have been found useful in the Beckmann rearrangement
of 4-HAP oxime to APAP and offer a viable alternative to SO₂. An important feature
of the ester solvent is the ability of the ester solvent to extract the 4-HAP oxime
from the reaction forming mixture. Accordingly, the oxime/solvent mixture can be directly
contacted with the Beckmann rearrangement catalyst without separation and crystallization
of the 4-HAP oxime.
[0008] The ester solvent is particularly useful not only because of its ability to extract
the 4-HAP oxime but also since the ester solvent is substantially water-immiscible,
forms a low-boiling azeotrope with water, can be dried easily by distillative removal
of water, and can be removed from water easily by distillation to allow for substantially
easier recovery and purification of the APAP product than is possible with SO₂ solvent.
[0009] It has been found, however, that the use of the ester solvent in the Beckmann rearrangement
of 4-HAP oxime to APAP tends to lead to the formation of by-product N-methyl-p-hydroxybenzamide
(MHBA). Accordingly, it would be useful to use the ester solvent for the Beckmann
rearrangement of 4-HAP oxime to APAP and overcome the problem of by-product formation
which has been found.
[0010] It is therefore the primary objective of the present invention to provide an alternative
solvent to SO₂ in the above-described Beckmann rearrangement reaction, which solvent
is less toxic, less volatile, and less corrosive; which reduces capital costs; and
which can greatly reduce the handling and operating costs of the two-step process
of forming APAP from 4-hydroxyacetophenone.
[0011] It is another object of this invention to provide for novel Beckmann rearrangement
catalysts which are particularly effective in reducing by-product formation upon use
of ester solvents for the reaction.
[0012] Still another object of this invention is to provide an effective and efficient method
of separation and purification of APAP product formed by the Beckmann rearrangement
of 4-HAP oxime in an ester solvent.
SUMMARY OF THE INVENTION
[0013] In accordance with the present invention, alkyl alkanoate esters are used as the
solvent for the Beckmann rearrangement of 4-hydroxyacetophenone oxime (4-HAP oxime)
to acetaminophen (APAP). The Beckmann rearrangement utilizes an appropriate acidic
catalyst such as thionyl chloride or phosphorus oxytrichloride. Novel acidic Beckmann
rearrangement catalysts which have a carbon atom as the active electrophilic site
are particularly advantageous for substantially reducing or eliminating formation
of the Beckmann rearrangement by-product N-methyl-p-hydroxybenzamide (MHBA) when the
above esters are used as the reaction solvent. These novel acidic Beckmann rearrangement
catalysts which have a carbon atom as the active electrophilic site include N-methylacetonitrilium
tetrafluoroborate, trifluoroacetic anhydride, or the Vilsmeier reagent prepared from
N,N-dimethylformamide (DMF) and thionyl chloride.
[0014] The Beckmann rearrangement may be carried out in the presence of potassium iodide,
which serves to minimize the formation of by-products which contaminate the APAP product.
Activated carbon may also be added to the mixture of 4-HAP oxime and ester solvent
to help prevent retention of color in the APAP product.
[0015] An important advantage of utilizing alkyl alkanoate esters as the solvent for the
Beckmann rearrangement of 4-HAP oxime to APAP is that the alkyl alkanoate esters can
be utilized to extract the 4-HAP oxime from the aqueous product which is formed from
the reaction of 4-HAP with hydroxylamine in the first step of the integrated process.
After removal of water, preferably by azeotropic distillation, the extracted 4-HAP
oxime and alkyl alkanoate ester mixture can be treated directly with an appropriate
acidic catalyst to effect Beckmann rearrangement. Another advantage of utilizing alkyl
alkanoate esters as the solvent for the Beckmann rearrangement of 4-HAP oxime to APAP
is that aqueous media can be used to assist removal of such solvents from the crude
solid APAP product.
DETAILED DESCRIPTION OF THE INVENTION
[0016] In accordance with this invention, N-acetyl-para-aminophenol (APAP) is produced by
reacting 4-hydroxyacetophenone (4-HAP) with hydroxylamine to form the ketoxime of
4-HAP and subjecting the ketoxime to a Beckmann rearrangement in the presence of an
alkyl alkanoate ester solvent and an appropriate acidic catalyst to form the N-acyl-hydroxyaromatic
amine.
[0017] The ketoxime formation proceeds as in equation (I):

[0018] The Beckmann rearrangement to form the desired APAP product proceeds as in equation
(II):

[0019] 4-Hydroxyacetophenone used to form the oxime may be prepared by any method known
in the art. For example, it may be prepared by the Fries rearrangement of phenyl acetate
or, alternatively, in a Friedel-Crafts acetylation of phenol. The catalyst for both
mentioned reactions is preferably hydrogen fluoride, but any other catalyst known
in the art to be effective for the Fries or Friedel-Crafts reactions may be used,
e.g., aluminum chloride, zinc chloride or boron trifluoride. A more detailed description
of methods of forming the hydroxyaromatic ketone are described in the aforementioned
U.S. 4,524,217.
[0020] The conversion of 4-HAP into the ketoxime by equation (I) is accomplished by contacting
the ketone with a hydroxylamine salt, e.g., hydroxylamine hydrochloride, hydroxylamine
sulfate, hydroxylamine bisulfate, or hydroxylamine phosphate, and a base, e.g. ammonium
hydroxide (aqueous ammonia), potassium hydroxide, sodium hydroxide, or lithium hydroxide.
Since hydroxylamine is sensitive and decomposes in its free form, it is commercially
supplied as one of its acid salts. The free hydroxylamine is liberated upon treatment
of the acid salt with the base. If sodium hydroxide or aqueous ammonia is used as
the base to liberate hydroxylamine from its acidic sulfate salt, then such liberation
also produces sodium or ammonium sulfate, respectively, as a by-product. In the integrated
process for producing APAP from 4-HAP (disclosed in detail below) wherein Beckmann
reaction solvent is used to extract 4-HAP oxime from the aqueous oximation mixture,
it is preferred to use a strong base such as the alkali metal hydroxides to liberate
the hydroxylamine.
[0021] The base should be used in an amount, for example, of 0.5 to 2 molar equivalents
per molar equivalent of starting hydroxylamine. The base is preferably used in an
amount of 0.8-1.0 molar equivalents per molar equivalent of starting hydroxylamine
so that a small amount of hydroxylamine remains in the form of its acid salt to create
a pH buffer that maintains the pH of the oximation reaction in the range of 3-7. Use
of larger amounts of base can cause the pH to rise above 7 and results in initiating
undesirable condensation reactions of 4-HAP and its oxime. The hydroxylamine acid
salt is preferably used in an amount of 1-2 molar equivalents of starting hydroxylamine
per mole of starting 4-HAP. Oximation is run at a temperature, for example of 0° to
200°C, for a period of from about 5 minutes to 4 hours. Any pressure may be used,
e.g., 80 mm of mercury to 20 atmospheres absolute. The reaction is preferably carried
out in an aqueous or alcoholic medium, i.e., in the presence of water and/or an alcohol
such as methanol, ethanol, or isopropanol.
[0022] The 4-HAP oxime is converted into APAP by a Beckmann rearrangement as shown in equation
(II) by contacting the ketoxime with an alkyl alkanoate ester solvent and an appropriate
acidic catalyst at a reaction temperature, for example, of from 0° to 100°C for a
period of from about 5 minutes to 4 hours. The pressure is not critical and may be,
for example, in the range of 1 mm of mercury to 10 atmospheres absolute. The Beckmann
rearrangement can be carried out quite successfully with large amounts of undissolved
4-HAP oxime solids and large amounts of undissolved APAP solids suspended in the reaction
mixture. The amount of reaction solvent should be sufficiently large so that any undissolved
solids form a slurry that settles under the force of gravity and is stirable, but
should not be so large as to prevent crystallization of the APAP product when the
reaction mixture is chilled. Thus, the reaction solvent should be present in amounts
of from about 0.75-50:1 by weight with respect to the 4-HAP oxime. The weight ratio
of oxime to Beckmann rearrangement catalyst ranges from about 5:1 up to about 300:1.
[0023] The Beckmann reaction is carried out to 4-HAP oxime conversions of preferably at
least about 50% and more preferably at least about 80% to minimize losses of unreacted
4-HAP oxime to recrystallization and wash liquors. Conversions of 4-HAP oxime during
Beckmann rearrangements can be controlled by use of an appropriate quantity of catalyst.
A certain quantity of catalyst gives substantially 100% 4-HAP oxime conversion; with
smaller amounts of catalyst, 4-HAP oxime conversions decrease with decreasing catalyst
quantity.
[0024] The process of this invention is preferably carried out by adding an alkali metal
iodide such as potassium iodide to the 4-hydroxyacetophenone oxime prior to carrying
out the Beckmann rearrangement in alkyl alkanoate ester solvent. Potassium iodide
serves to minimize formation of by-products that can contaminate the APAP product.
The amount of alkali metal iodide utilized is extremely small and very acceptable
results have been obtained when using 0.2 wt% of potassium iodide relative to the
oxime. It should be realized that no particular advantage is gained in going over
the 0.2 gram KI per 100 grams of 4-hydroxyacetophenone oxime but, obviously, such
can be done if desired. The amount of inorganic iodide which should be added is that
amount sufficient to substantially prevent the formation of chlorinated by-products
and said amount is usually in the range varying from about 0.02 gram to about 2.0
grams of potassium iodide per 100 grams of 4-hydroxyacetophenone oxime which is subjected
to the Beckmann rearrangement.
[0025] The manner in which iodide is added to the Beckmann rearrangement reactor is by no
means critical. Iodide can be added directly to the reactor or can be contained in
a recycle stream of the reaction mixture solvent. A more detailed description of potassium
iodide addition to the Beckmann rearrangement reactor is given in commonly assigned,
U.S. Patent No. 4,855,499, the entire content of which is herein incorporated by reference.
[0026] Activated carbon may also be added to the Beckmann rearrangement reaction mixture
in a manner to be described later in more detail.
[0027] Appropriate acidic catalysts for use in the Beckmann rearrangement of 4-hydroxyacetophenone
oxime to APAP include, but are not limited to, thionyl chloride; methanesulfonyl chloride;
trifluoromethanesulfonyl chloride; methanesulfonic anhydride; the mixed anhydride
of trichloroacetic and methanesulfonic acids; p-toluenesulfonic anhydride; phosphorus
oxytrichloride; phosphorus pentoxide; phenylphosphonic dichloride; diphenylphosphinic
chloride; trifluoroacetic anhydride; trichloroacetic anhydride; trifluoroacetyl chloride;
trichloroacetyl chloride; oxalyl chloride; ethyl oxalyl chloride; phosgene; trichloromethyl
chloroformate (diphosgene); methyl chloroformate; N,N-dimethylcarbamyl chloride; nitrilium
salts of the formula (R′C≡N⁺R′′)X⁻, where R′ and R′′ can each independently be alkyl
such as methyl, isopropyl or substituted alkyl, aryl, or substituted aryl and where
X⁻ can be BF₄⁻, SbF₆⁻, PF₆⁻, FeCl₄⁻, AlCl₄⁻, Cl⁻ , Br⁻ , or I⁻; and any Vilsmeier
reagent prepared from a carboxylic acid amide (such as N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA), or N-methylpyrrolidinone (NMP)) and a reagent capable
of replacing oxygen with halogen (such as thionyl chloride, phosphorus oxytrichloride,
phosphorus pentachloride, trichloroacetyl chloride, trichloromethyl chloroformate
(diphosgene), or phosgene).
[0028] For the purposes of the present specification and claims, the term "catalyst" includes
any material capable of initiating Beckmann rearrangement of 4-HAP oxime to APAP.
The Beckmann rearrangement might be described formally as the chain-reaction process
depicted in the following equation (III):

In equation (III), 4-HAP oxime is converted to chain intermediate I with simultaneous
conversion of species X to species Y. Examples of species X and corresponding species
Y are shown in the following table:

[0029] The first five entries for species X in the above table, respectively thionyl chloride,
phosphorus oxytrichloride, Vilsmeier reagent N,N-dimethylchloroformiminium cation,
trifluoroacetic anhydride, and N-methylacetonitrilium cation, are herein nominally
referred to as Beckmann rearrangement "catalysts." Assuming the role of species X
in the above equation (III), such "catalysts" initiate the Beckmann rearrangement
by converting 4-HAP oxime to chain intermediate I. Chain intermediate I (as species
X) is then converted to APAP (as species Y) with simultaneous regeneration of chain
intermediate I from 4-HAP oxime.
[0030] The active electrophilic site of a Beckmann rearrangement catalyst is the atom of
the catalyst at which the catalyst reacts with an oxime. With catalysts such as thionyl
chloride or phosphorus oxytrichloride that have a sulfur atom or a phosphorus atom
as the active electrophilic site, it has been found that Beckmann rearrangement of
4-HAP oxime in ester solvents produces small amounts of N-methyl-p-hydroxybenzamide
(MHBA) by-product. The MHBA by-product is only partially removed from the desired
APAP product by conventional purification techniques such as aqueous recrystallization.
[0031] In comparison to catalysts that have a sulfur or phosphorus atom as the active electrophilic
site, Beckmann catalysts having a carbon atom as the active electrophilic site can
offer the advantage of producing substantially less MHBA by-product during Beckmann
rearrangement of 4-HAP oxime to APAP in ester solvents. For example, no MHBA by-product
is formed during Beckmann rearrangement of 4-HAP oxime to APAP in ester solvents with
catalysts such as trifluoroacetic anhydride, trichloroacetic anhydride, or N-methylacetonitrilium
tetrafluoroborate, all of which have a carbon atom as the active electrophilic site
and none of which produces HCl or Cl⁻ as a by-product.
[0032] Catalysts that have a carbon atom as the active electrophilic site but that produce
HCl or Cl⁻ on reaction with 4-HAP oxime include trifluoroacetyl chloride, trichloroacetyl
chloride, oxalyl chloride, ethyl oxalyl chloride, phosgene, trichloromethyl chloroformate
(diphosgene), methyl chloroformate, N,N-dimethylcarbamyl chloride, and any Vilsmeier
reagent prepared from a carboxylic acid amide (such as N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA), or N-methylpyrrolidinone (NMP)) and a reagent capable
of replacing oxygen with halogen (such as thionyl chloride, phosphorus oxytrichloride,
phosphorus pentachloride, trichloroacetyl chloride, trichloromethyl chloroformate
(diphosgene), or phosgene). Such catalysts, in comparison to catalysts that have a
sulfur or phosphorus atom as the active electrophilic site, still can offer the advantage
of producing substantially less MHBA by-product during Beckmann rearrangement of 4-HAP
oxime to APAP in ester solvents. The advantage is particularly found when the Beckmann
rearrangement is run to a 4-HAP oxime conversion of no more than about 95% or when
an appropriate base is incorporated with the catalyst or the Beckmann reaction mixture.
Bases capable of reducing the amount of MHBA produced during the Beckmann reaction
include tertiary amines (such as pyridine or trialkylamine, e.g., triethylamine),
carboxylic acid salts (such as sodium acetate or sodium trifluoroacetate), phosphate
salts (such as ammonium dihydrogen phosphate), sodium metabisulfite, or surfactant
salts (such as sodium dodecyl sulfate). Such bases presumably serve to scavenge HCl
without destroying catalyst activity.
[0033] In the absence of such a base, MHBA formation accelerates with increasing 4-HAP oxime
conversion and accelerates sharply at 4-HAP oxime conversions above about 95% with
catalysts that have a carbon atom as the active electrophilic site but that produce
HCl or Cl⁻ on reaction with 4-HAP oxime. With such catalysts, it is therefore preferable
to use an appropriate base or to limit 4-HAP oxime conversion to about 95% or less
by use of an appropriate quantity of catalyst.
[0034] Use of bases (that presumably scavenge HCl without destroying catalyst activity)
also can reduce the amount of MHBA produced in thionyl chloride-catalyzed Beckmann
rearrangement of 4-HAP oxime to APAP in ester solvents.
[0035] The reaction solvent used in this invention is, as previously discussed, preferably
an alkyl ester of an alkanoic acid. Preferably the alkylester group has 1 to 6 carbon
atoms and the alkanoic acid contains 2 to 6 carbon atoms. Specific nonlimiting examples
of alkyl alkanoate esters that have proven useful in the present invention include
ethyl acetate, n-butyl acetate, methyl n-hexanoate, and n-hexyl acetate. A preferred
solvent is made from alkyl esters of acetic acid. Acetate esters have the advantage
of rendering degenerate any possible alkanoate exchange between the alkyl alkanoate
ester and the N-acetyl-p-aminophenol product.
[0036] The use of alkyl alkanoate esters as the Beckmann rearrangement solvent is advantageous
inasmuch as the Beckmann rearrangement can be carried out continuously or batchwise
with a centrifuge rather than batchwise with a Nutsche (e.g. Rosemund) filter which
is required utilizing SO₂ as the solvent. Alkyl alkanoate esters are much less volatile,
less toxic, and less corrosive than sulfur dioxide and therefore avoid the previously
described disadvantages of sulfur dioxide. Another important advantage of utilizing
an alkyl alkanoate ester as the solvent is that the crystallization, isolation, drying,
transport, handling, and storage of solid 4-HAP oxime can be eliminated by extracting
4-HAP oxime directly from the oximation product stream with the alkyl alkanoate ester,
removing water from the resulting alkyl alkanoate ester solution of oxime, and adding
an appropriate Beckmann rearrangement catalyst to the resulting dry mixture of oxime
and alkyl alkanoate ester.
[0037] Although extraction of 4-HAP oxime with an alkyl alkanoate ester extraction solvent
is preferably carried out on hot oximation product to prevent crystallization of 4-HAP
oxime and to avoid the expense of a cooling step, the extraction can also be carried
out on a chilled aqueous oximation product in which the 4-HAP oxime product has crystallized.
In either case, mixing of the alkyl alkanoate ester extraction solvent with the aqueous
oximation product yields two liquid phases: an upper liquid organic phase comprising
the alkyl alkanoate ester and 4-HAP oxime, and a lower aqueous phase comprising water
and the salt which is formed during liberation of the hydroxylamine. The weight ratio
of extraction solvent to 4-HAP oxime product is preferably about 0.5-25:1 and is more
preferably about 0.5-5:1. The aqueous phase thus obtained may be extracted with the
alkyl alkanoate ester extraction solvent one or more times to recover additional 4-HAP
oxime. Alternatively, the extraction of aqueous oximation product with alkyl alkanoate
ester extraction solvent may be carried out continuously in a York-Scheibel countercurrent-type
extractor.
[0038] The upper liquid organic phases are dried, preferably by distillative removal of
water as a low-boiling azeotrope with the alkyl alkanoate ester extraction solvent.
The alkyl alkanoate ester extraction solvent is preferably substantially immiscible
with water. Under this circumstance, most of the water and most of the ester distilled
from the 4-HAP oxime mixture will separate into different liquid phases. The distillate
ester phase can be decanted off the distillate aqueous phase and recycled to the mixture
of 4-HAP oxime and ester during the distillative removal of water. Most of the water
present in the mixture of ester and 4-HAP oxime prior to distillation can be removed
as a separate, relatively pure aqueous phase of the distillate. The distillation residue,
which comprises a substantially dry mixture of 4-HAP oxime and alkyl alkanoate ester
extraction solvent, can then be treated directly with an appropriate acidic catalyst
to effect Beckmann rearrangement to APAP.
[0039] If the oxime is to be extracted with an alkyl alkanoate ester, it has been found
that the use of a strong base such as sodium hydroxide has an important advantage
over relatively weak bases such as ammonium hydroxide (aqueous ammonia) in the first
stage of the process wherein is provided the liberation of free hydroxylamine from
a corresponding acid salt such as hydroxylammonium sulfate. The disadvantage of weak
bases such as ammonium hydroxide is that their use causes rearrangement of 4-HAP oxime
to acetaminophen and hydrolysis of acetaminophen and 4-HAP oxime to p-aminophenol
and 4-HAP, respectively, during the distillative drying of the extracted oxime. Traces
of the acid salt corresponding to the weak base, for example, ammonium sulfate, presumably
catalyze these undesirable side reactions during the distillative drying step. Furthermore,
previously useful purification techniques failed to give an acceptable acetaminophen
product when a relatively weak base such as ammonium hydroxide was used to liberate
free hydroxylamine. Use of strong bases such as sodium hydroxide avoids the undesirable
side reactions and permits successful purification of the crude acetaminophen product
by previously disclosed methods. The by-products produced with a strong base, for
example, sodium sulfate and water from sodium hydroxide, apparently do not catalyze
undesirable reactions during the distillative drying step.
[0040] Addition of activated carbon to the mixture of 4-HAP oxime and ester solvent has
been found to prevent substantial amounts of color from being retained in the APAP
product from subsequent Beckmann rearrangement. The activated carbon is preferably
added before addition of the Beckmann rearrangement catalyst. If the mixture of 4-HAP
oxime and ester solvent is dried by azeotropic distillation, the activated carbon
is preferably added before or during the azeotropic distillation. The activated carbon
is preferably removed from the APAP product by dissolving the APAP product in hot
water, filtering the activated carbon off the resulting aqueous solution of APAP,
and cooling the aqueous filtrate to recrystallize the APAP product. Prevention of
color retention in the APAP product by such use of activated carbon is particularly
significant when ester Beckmann reaction filtrates are recycled. Such use of activated
carbon prevents retention of color that cannot be removed by other means after the
Beckmann reaction.
[0041] In preferred embodiments, the acetaminophen product is purified by neutralization
with aqueous base and recrystallization from an aqueous medium. The ester solvent
is removed from the acetaminophen product prior to recrystallization in the aqueous
medium. The ester solvent can be removed from the acetaminophen by any of several
methods, including, individually or in combination, filtration, washing filtered acetaminophen
product with water, evaporation of solvent to a solid residue, and water-assisted
distillative removal of ester.
[0042] Filtration of ester Beckmann reaction mixtures yields a filter cake of solid acetaminophen
and an ester filtrate liquor that can be recycled to a subsequent Beckmann reaction.
The filter cake of solid acetaminophen contains residual ester solvent that is preferably
removed prior to recrystallization of the acetaminophen from an aqueous medium. The
residual ester in the filter cake can be removed by evaporation and then recovered
by condensation. However, substantially complete evaporation and recovery of residual
ester solvent can consume considerable time and utilities such as vacuum, steam, cooling
water, etc. The substantially ester-free filter cake can then be neutralized in an
aqueous slurry with aqueous base.
[0043] Alternatively, residual ester Beckmann liquor can be washed from the APAP filter
cake with an aqueous medium such as the mother liquor from a recrystallization of
a previous batch of APAP or, preferably, the aqueous phase resulting from extraction
of a crude oximation product with alkyl alkanoate ester solvent. Such washing dislodges
the residual ester from the solid APAP by mechanical entrainment. The resulting wash
liquors, on standing, separate into two phases, one of which (usually the top phase)
is residual ester that can be separated and recovered. The other phase (usually the
lower one) is an aqueous medium that can be used for further or other APAP filter
cake washing operations. Use of the aqueous phase resulting from extraction of a crude
oximation product is preferred in such APAP filter cake washing because this aqueous
phase's high content of dissolved salts reduces the solubilities of ester and acetaminophen
in the aqueous phase and the solubilities of water and acetaminophen in the ester
phase.
[0044] With this aqueous washing procedure, neutralization can be carried out with aqueous
base either before or after filtration of the Beckmann reaction mixture. The neutralization
is preferably carried out with the same aqueous medium that is used to wash the acetaminophen
filter cake. If neutralization is carried out before filtration, the aqueous medium
and the aqueous base are preferably mixed with the crude Beckmann reaction slurry
inside the Beckmann reactor. The resulting neutralized slurry can then be filtered
in its entirety to provide a filter cake of neutralized acetaminophen still containing
some residual ester. Conducting neutralization before filtration has the advantage
of reducing the metallurgical requirements (and cost) of the filter. If neutralization
is carried out after filtration, the acetaminophen filter cake is slurried in an aqueous
medium, aqueous base is added, and the resulting neutralized slurry is filtered.
[0045] If neutralization is carried out before residual ester is washed off the acetaminophen
filter cake, the residual ester can be recovered by allowing the neutralization liquor
filtrate to separate into an ester phase and an aqueous phase, the latter of which
can be used for further or other acetaminophen filter cake washing operations.
[0046] As an alternative to or in conjunction with the evaporation or washing procedures
just described, the acetaminophen filter cake can be slurried in an aqueous medium
to assist distillative removal of residual ester. As yet another alternative, filtration
of the ester Beckmann reaction mixture can be avoided completely, permitting conversion
of 4-HAP to recrystallized acetaminophen in a single vessel, by addition of an aqueous
medium to the ester Beckmann reaction mixture to assist distillative removal of ester
solvent. The ester solvent employed for the Beckmann reaction preferably forms a low-boiling
azeotrope with water. Distillation of the mixture of acetaminophen, aqueous medium,
and ester removes the ester from a residual aqueous mixture of acetaminophen. The
aqueous medium used to assist distillative removal of ester is preferably the same
as that used for neutralization, is preferably the same as that used for recrystallization,
and is preferably the same as that used for neutralization and recrystallization.
[0047] As a means for removal of the last portions of ester solvent from acetaminophen product,
water-assisted distillation is preferred to evaporation in the absence of water. Water-assisted
distillative removal offers more efficient mixing and heat transfer, and, for reasons
including these, can be carried out at lower temperatures, in less time, and with
less consumption of utilities. These advantages are particularly great when distillative
removal of ester is assisted with water vapor (i.e, steam) passed directly into the
acetaminophen/ester mixture. The ability to remove ester at lower temperatures avoids
formation of undesirable by-products and impurities.
[0048] However, distillative removal of the first portions of ester solvent from acetaminophen
product might preferably be done in the absence of water to avoid losses of heat to
vaporization of water. Distillative removal of ester solvent permits elimination of
filtration, elimination of ester Beckmann reaction liquor recycle, and elimination
of the resulting build-up of colored impurities.
[0049] Subsequent to the recovery of the product of the Beckmann rearrangement, the ester
solvent can be recycled to either the Beckmann rearrangement or to the oxime extraction.
[0050] The invention will be further illustrated by the following nonlimiting examples.
EXAMPLE 1
[0051] A slurry of 4-HAP oxime (100.00 g, 0.6617 mols) and potassium iodide (0.200 g) in
ethyl acetate (185 mL) was stirred and heated to 50° C under nitrogen (290 torr absolute
total pressure). A solution of thionyl chloride (1.0 mL, 1.631 g, 13.71 mmole) in
ethyl acetate (15 mL) was then added over 25 minutes to the stirred 4-HAP oxime/ethyl
acetate slurry. The temperature of the reaction mixture was maintained at 50-51° C
by allowing the heat of reaction to reflux the ethyl acetate solvent under 290 torr
absolute total pressure. Within about ten minutes after the start of the thionyl chloride
addition, the reaction mixture was a nearly homogeneous, light amber liquid. White
solid APAP then began to precipitate. The refluxing started to subside after about
90% of the thionyl chloride had been added. After the thionyl chloride addition was
completed, the reaction mixture was allowed to cool to 40° C over about ten minutes
and was then chilled in an ice bath to 3° C. The reaction slurry was filtered under
nitrogen to give a cake of light yellow Beckmann reaction solids and a filtrate of
yellow Beckmann reaction liquor. Residual ethyl acetate was pumped off the reaction
solids at 0.025 torr and ambient temperature. The dried reaction solids were then
purified by known washing, filtering and recrystallization procedures. Results are
shown in Table 1. The solid filter material used in the purification was dried under
vacuum (0.025 torr) at ambient temperature to a mass 3.53 g greater than the weight
of the starting filter material; this mass increase presumably was due mostly to adsorbed
APAP. Throughout the entire preparation, the crude APAP solids and purified APAP solids
were granular, free of tackiness, and easily handled.
EXAMPLE 2
[0052] The preparation of Example 1 was repeated with the starting 4-HAP oxime/ethyl acetate
slurry containing 90 mL instead of 185 mL of ethyl acetate. Under these conditions,
the reaction mixture contained substantial amounts of white solid throughout the entire
reaction period. As the refluxing subsided near completion of the thionyl chloride
addition, the reaction slurry became so viscous that it no longer settled under the
force of gravity. Throughout the entire preparation, the crude APAP solids and purified
APAP solids were granular, free of tackiness, and easily handled. Results are shown
in Table 1.
EXAMPLE 3
[0053] The preparation of Example 1 was repeated with the starting 4-HAP oxime/ethyl acetate
slurry containing 475 mL instead of 185 mL of ethyl acetate. This volume of ethyl
acetate was sufficient to dissolve essentially all of the starting 4-HAP oxime at
25° C. The reaction mixture remained essentially homogeneous until about one-third
of the thionyl chloride catalyst had been added, at which time the APAP product started
to precipitate as a white solid. Throughout the entire preparation, the crude APAP
solids and purified APAP solids were granular, free of tackiness, and easily handled.
Results are shown in Table 1.
EXAMPLE 4
[0054] The preparation of Example 1 was repeated without KI. The crude and purified APAP
products were noticeably more colored than their counterparts from Example 1. Throughout
the entire preparation, the crude APAP solids and purified APAP solids were granular,
free of tackiness, and easily handled. Results are shown in Table 1.
EXAMPLE 5
[0055] The preparation of Example 1 was repeated with the Beckmann reaction being run at
32 °C under 150 torr absolute total pressure. Throughout the entire preparation, the
crude APAP solids and purified APAP solids were granular, free of tackiness, and easily
handled. Results are shown in Table 1.
EXAMPLE 6
[0056] The preparation of Example 1 was repeated with the following modifications. In the
starting 4-HAP oxime/ethyl acetate slurry, the ethyl acetate Beckmann reaction liquor
from the preparation of Example 1 was used in place of 185 mL of fresh ethyl acetate.
The catalyst solution consisted of thionyl chloride (1.3 mL instead of 1.0 mL) in
fresh ethyl acetate (50 mL instead of 15 mL to make up the ethyl acetate loss in the
drying step of Example 1). Fresh, acid-washed activated carbon (0.500 g) was now also
included with the starting 4-HAP oxime/ethyl acetate slurry. The dried reaction solids
were purified by known methods. Throughout the entire preparation, the crude APAP
solids and purified APAP solids were granular, free of tackiness, and easily handled.
Results are shown in Table 1.
EXAMPLE 7
[0057] To a stirred solution of 4-HAP (100.00 g) and hydroxylamine sulfate (63.6 g) in water
(370 mL) heated to 80° C was added a solution of sodium hydroxide (30.5 g) in water
(100 mL) over five minutes. The stirred, homogeneous, yellow reaction mixture was
refluxed at 102-103° C under air for 20 minutes and then cooled to 25° C. Ethyl acetate
(200 mL) was then added to the cooled reaction mixture, which contained a large amount
of crystallized 4-HAP oxime. The three-phase mixture was shaken well for about half
a minute and then allowed to settle. Two liquid phases separated completely within
about one minute, leaving only a small amount of undissolved solid. The bottom aqueous
phase and the undissolved solids were separated from the upper ethyl acetate phase
and then extracted with two more 100 mL portions of ethyl acetate.
[0058] The three ethyl acetate extracts were combined and dried by azeotropic distillation
under nitrogen at atmospheric pressure in two steps. The first step, which employed
a Dean-Stark trap under conditions of total reflux, removed 34.5 mL of aqueous phase
distillate. The second step, which employed a 10-tray Oldershaw column and a reflux
to takeoff ratio of 3:1, yielded 200 mL of cloudy distillate and a stable final overhead
temperature of 77.1° C. The distillates were found by analysis to contain less than
0.02 wt % each of acetic acid and ethanol.
[0059] On cooling, 4-HAP oxime crystallized from the amber distillation residue. The resulting
dry slurry of 4-HAP oxime in ethyl acetate was then subjected to the conditions of
the Beckmann rearrangement described in Example 1 using 0.200 g of KI, 85 mL of fresh
additional ethyl acetate, and a catalyst solution of thionyl chloride (1.3 mL) in
ethyl acetate (15 mL). Throughout the entire preparation, the crude APAP solids and
purified APAP solids were granular, free of tackiness, and easily handled. Results
are shown in Table 1.
EXAMPLE 8
[0060] The oximation/Beckmann reaction sequence of Example 7 was repeated with only one
significant modification now described. The aqueous reaction mixture from the oximation
reaction was drained hot (about 100° C) over five minutes into a round bottom flask
containing ethyl acetate (200 mL) and equipped with a reflux condenser. The ethyl
acetate refluxed very gently under atmospheric pressure for only a short period during
the addition. When the addition was complete, the mixture was at about 73° C and was
mixed well by stirring vigorously for about one minute. Two homogeneous liquid phases
then separated completely within about one minute, leaving no undissolved solids.
The lower (aqueous) phase was extracted with two more 100 mL portions of ethyl acetate
as described in Example 7.
[0061] The distillates from the azeotropic drying steps were found by analysis to contain
less than 0.02 wt % each of ethanol and acetic acid. Throughout the entire preparation,
the crude APAP solids and purified APAP solids were granular, free of tackiness, and
easily handled. Results are shown in Table 1.
EXAMPLE 9
[0062] The oximation/Beckmann rearrangement reaction sequence of Example 7 was repeated
with 29 wt % aqueous ammonia (60 mL) being used instead of aqueous sodium hydroxide
as the base to liberate free hydroxylamine during the oximation. Results are shown
in Table 1.
EXAMPLE 10
[0063] The oximation/Beckmann rearrangement sequence of Example 8 was repeated with the
following modifications. Instead of 370 mL of fresh water, the oximation used 148
mL of fresh water and 222 mL of the aqueous phase remaining after extraction of the
oximation product of Example 8 with ethyl acetate. Instead of being drained into 200
mL of fresh ethyl acetate, the hot oximation product was drained into the ethyl acetate
Beckmann reaction liquor recovered from the preparation of Example 8. Extraction of
the oximation product was then completed with two 100 mL portions of the wet ethyl
acetate distilled off the ethyl acetate extracts of Example 8. For the Beckmann rearrangement,
the ethyl acetate solution of thionyl chloride used 50 mL of fresh ethyl acetate instead
of 15 mL to make up the ethyl acetate loss in the drying step of Example 8. Fresh,
acid-washed activated carbon (0.50 g) was now also included with the starting 4-HAP
oxime/ethyl acetate slurry. After removal of residual ethyl acetate, the dried reaction
solids were purified by known methods.
[0064] The distillates from the azeotropic drying steps were found by analysis to contain
no more than 0.032 wt % each of ethanol and acetic acid. Throughout the entire preparation,
the crude APAP solids and purified APAP solids were granular, free of tackiness, and
easily handled. Results are shown in Table 1.
EXAMPLE 11
[0065] A slurry of 4-HAP oxime (100.00 g, 0.6617 moles) in n-hexyl acetate (450 mL) containing
no potassium iodide was stirred and heated to 60° C under nitrogen (8 torr absolute
total pressure). A solution of thionyl chloride (1.3 mL, 2.120 grams, 17.82 mmole)
in n-hexyl acetate (50 mL) was then added over 30 minutes to the stirred 4-HAP oxime/n-hexyl
acetate slurry. The temperature of the reaction mixture was maintained at 58-65° C
by allowing the heat of reaction to reflux the hexyl acetate solvent under 8 torr
absolute total pressure. Within about five minutes after the start of the thionyl
chloride addition, the reaction mixture was a nearly homogeneous amber liquid. Pale
yellow solid APAP then precipitated during the remainder of the thionyl chloride addition.
The refluxing started to subside after about 90% of the thionyl chloride had been
added. After the thionyl chloride addition was completed, the reaction mixture was
chilled in an ice bath to 5° C. The reaction slurry was filtered under nitrogen to
give a cake of golden yellow Beckmann reaction solids and a filtrate of yellow Beckmann
reaction liquor. Residual n-hexyl acetate was pumped off the reaction solids at 0.025
torr and ambient temperature. The dried reaction solids were then purified by known
washing, filtration, and recrystallization procedures. The results shown in Table
1 do not include 2.85 g of 98.8% pure APAP that precipitated from the yellow Beckmann
reaction liquor on standing overnight at room temperature under air. Throughout the
entire preparation, the crude APAP solids and purified APAP solids were granular and
handled without problem.
EXAMPLE 12
[0066] The preparation of Example 11 was repeated at 50° C and 17 torr total absolute pressure
with methyl n-hexanoate instead of n-hexyl acetate as the reaction solvent. Throughout
the entire preparation, the crude APAP solids and purified APAP solids were granular
and handled without problem. Results are shown in Table 1.
EXAMPLE 13-112
[0067] Examples 13-112 describe Beckmann rearrangement of 4-HAP oxime to APAP with a variety
of catalysts, some of which produce little or no MHBA. Specific conditions and results
for Examples 13-112 are shown in Tables 2-11. The following general procedure was
used for Examples 13-112. The indicated amounts of the indicated catalyst components
were mixed with typically 20-25 mL of ethyl acetate at room temperature. The resulting
catalyst mixtures were added at room temperature from an addition funnel to a stirred
slurry of 4-HAP oxime (about 100 g), potassium iodide (about 0.2 g), the indicated
amounts of the indicated additives, and ethyl acetate (about 200 mL) heated to reflux
at about the indicated temperature inside a nitrogen-purged reaction vessel. The indicated
temperatures were achieved by adjustment of the reaction vessel's pressure, which
was typically maintained at less than one atmosphere absolute. The reaction vessel
was equipped with a 9° C water-cooled condenser to reflux the ethyl acetate vapors.
The catalyst mixtures were added (typically over 15-30 minutes) at a rate sufficient
to maintain ethyl acetate reflux within the capacity of the condenser. The indicated
reaction temperature was maintained for the indicated reaction time either with the
heat of the Beckmann rearrangement or, if this was insufficient, with heat applied
to the exterior bottom surface of the reaction vessel. The reaction mixtures were
cooled to 0-25° C under nitrogen and then filtered. The oxime conversions, oxime accountabilities,
and APAP and MHBA efficiencies and yields shown in Tables 2-11 are all based on both
analyses of the ethyl acetate filtrates and analyses of the filtered solids.
[0068] In Example 19, 0.50 g of KI was used instead of 0.20 g.
[0069] In Example 25, the catalyst mixture was prepared by dropwise addition of the SO₃
to a stirred, 0° C solution of the methanesulfonic acid in ethyl acetate (20 mL).
[0070] In Example 29, the reaction was carried out on half the scale indicated above and
in Table 3. A slurry of potassium 4-HAP oxime-O-sulfonate (2.3 g) in ethyl acetate
(60 mL) was added as catalyst over 7 minutes to a 48° C slurry of 4-HAP oxime (50.0
g), KI (0.1 g), sulfuric acid (1.50 g), and ethyl acetate (100 mL). The reaction mixture
was then heated to 70° C and stirred at this temperature for 102 minutes before being
allowed to cool to room temperature.
[0071] In Examples 37 and 40, n-butyl acetate was used instead of ethyl acetate throughout,
no potassium iodide war used, and the reactions were carried out on twice the scale
indicated above and in Tables 4 and 5. In Example 37, neat BF₃·Et₂O catalyst was added
to the oxime slurry without dilution. Examples 40 and 122 are in fact identical, and
the procedure for these Examples is detailed below for Example 122. The procedure
for recovery of recrystallized APAP product in Example 37 was the same as that for
Example 122 below.
[0072] In Examples 26, 29, 37, and 38, the entire catalyst mixture was added to an about
50° C 4-HAP oxime slurry over 7-45 minutes before the Beckmann reaction temperature
was increased to the indicated level.
[0073] In Example 39, the ((AcO)₂B)₂O catalyst was incorporated with the original mixture
of 4-HAP oxime and ethyl acetate in the reaction vessel before heating.
[0074] In Examples 45 and 46, the catalyst mixture was stirred and maintained at about 0-4°
C throughout its entire preparation and until its use as Beckmann rearrangement catalyst.
A solution of the indicated amount of CCl₃COCl in ethyl acetate (7 mL in Example 45
and 15 mL in Example 46) was added over 20 minutes (Example 45) or 30 minutes (Example
46) to a stirred solution of the indicated amount of 4-HAP oxime in ethyl acetate
(20 mL in Example 45 and 35 mL in Example 46). In Example 45, an additional 10 mL
of 0-4° C ethyl acetate was added to the catalyst mixture midway into the CCl₃COCl
addition. After completion of the CCl₃COCl addition, the resulting mixture was stirred
for about 10 minutes before dropwise addition of the indicated amount of triethylamine
(neat in Example 45 and as a solution in 5 mL of ethyl acetate in Example 46) over
about 10 minutes. The resulting mixture was then stirred for about 2 hours before
use as Beckmann rearrangement catalyst. The catalyst mixture is believed to have contained
4-HAP oxime-O-trichloroacetate as the active species. In Example 45, 100.0 g of 4-HAP
oxime slurried in 190 mL of ethyl acetate was used for Beckmann rearrangement. In
Example 46, 94.7 g of 4-HAP oxime slurried in 165 mL of ethyl acetate was used for
Beckmann rearrangement.
[0075] In Example 47, the catalyst mixture was stirred overnight at room temperature prior
to use as the Beckmann rearrangement catalyst.
[0076] In Example 48, the triethylamine (3.5 g) was added dropwise over 5 minutes to a stirred
solution of the trifluoroacetic acid (4.0 g) in 50 mL of the ethyl acetate before
addition of the remaining ethyl acetate (150 mL) and the 4-HAP oxime (100.0 g).
[0077] In Examples 61-67, 70-83, and 87-98, the indicated catalyst components were combined
about 30 minutes prior to use as the Beckmann rearrangement catalyst. While standing
at room temperature with agitation about once every ten minutes during this approximately
30 minute period, the indicated components of the catalyst mixture are believed to
have reacted to produce Vilsmeier reagents. Vilsmeier reagents are also believed to
have been produced in the catalyst mixtures for Examples 84-86, which were stirred
at room temperature for about 18 hours before use as Beckmann catalysts. In Example
66, the catalyst mixture was prepared with 20 mL of tetrahydrofuran in addition to
20 mL of ethyl acetate. Formation of the Vilsmeier reagent from dimethylformamide
and thionyl chloride in Examples 61-67 was indicated by its precipitation as colorless
crystals. Most of these crystals were added from the addition funnel to the Beckmann
reaction mixture as a suspension in the original catalyst mixtures. Most of the crystals
remaining in the addition funnel were then added to the Beckmann reaction mixture
after resuspension in an additional about 15 mL of ethyl acetate. The other Vilsmeier
reagents did not precipitate.
[0078] In Example 82, 93.2 g of 4-HAP oxime was charged to the reaction vessel. The methanesulfonic
acid and the sodium salt of 4-HAP oxime are believed to have reacted to produce sodium
methanesulfonate and additional 4-HAP oxime
in situ.
EXAMPLES 113-118
[0079] In Examples 113-118, oximation and Beckmann reactions were integrated with ethyl
acetate according to the procedure described immediately below and in Table 12.
[0080] To a stirred mixture of 4-HAP (100.0 g), hydroxylamine sulfate (63.6 g), and water
(191 mL) heated to 80° C was added a solution of sodium hydroxide (30.5 g) in water
(122 mL) over a period not longer than 30 seconds. The resulting stirred mixture was
then refluxed under air at about 103° C for 45-60 minutes before adding 223-318 g
of ethyl acetate (either fresh or the distillate from a previous batch's azeotropic
drying step). Reflux of ethyl acetate/water azeotrope cooled the stirred mixture to
about 70° C. After having been stirred for about three minutes, the hot, solid-free
mixture was allowed to separate into two liquid phases. The hot, solid-free aqueous
phase was drained from the hot, solid-free ester phase, to which was added the ethyl
acetate filtrate (123.0 - 284.0 g) from the previous batch's Beckmann reaction mixture.
This ethyl acetate filtrate contained APAP, 4-HAP oxime, and 4-HAP as its most significant
solutes.
[0081] The resulting 4-HAP oxime/ethyl acetate mixture was dried by azeotropic distillation
as follows. The 4-HAP oxime/ethyl acetate mixture was stirred and refluxed under nitrogen
at about 58-64° C and about 400 torr absolute pressure while 39.42 - 61.35 g of aqueous
phase was removed from the reflux condensate with a Dean-Stark trap. After addition
of KI (0.200 g) and fresh make-up ethyl acetate (45-225 g), azeotropic drying of the
stirred 4-HAP oxime/ethyl acetate mixture was then continued by distillation through
a 1′′ diameter, ten-tray Oldershaw column under nitrogen at about 400 torr absolute
pressure with a 3:1 or a 1:1 reflux:take-off ratio. While 220-440 mL of ethyl acetate
distillate was collected, the temperature of the undistilled residue rose from about
64° C to about 75° C. The resulting undistilled residue was a substantially dry 4-HAP
oxime/ethyl acetate mixture.
[0082] In Example 113, an aqueous slurry consisting of activated carbon (1.00 g), sodium
dithionite (0.10 g), and water (2.2 mL) was added to the wet 4-HAP oxime/ethyl acetate
mixture just before azeotropic drying with the Dean Stark trap was started. In Examples
114, 115, 117, and 118, activated carbon (1.0 g) was added to the 4-HAP oxime/ethyl
acetate mixture after azeotropic drying with the Dean Stark trap had been completed
and before azeotropic drying with the Oldershaw column was started.
[0083] A solid Vilsmeier reagent was prepared by stirring DMF (1.3-2.3 mL) and thionyl chloride
(0.8-1.3 mL) in ethyl acetate (15-30 mL) at about 23° C under nitrogen for about 20
minutes. The ethyl acetate suspension of the solid Vilsmeier reagent was then added
as the Beckmann reaction catalyst in about 15 portions over about 30 minutes to the
4-HAP oxime/ethyl acetate mixture dried by azeotropic distillation. During the catalyst
addition, the Beckmann reaction mixture was stirred under air-free conditions at a
temperature of about 45-51° C maintained by ethyl acetate reflux at about 228 torr
absolute pressure. After all catalyst had been added, the stirred Beckmann reaction
mixture was allowed to cool to about 40° C over about 15 minutes before being chilled
to about 25° C.
[0084] In Examples 113-115, the acetaminophen product was neutralized after filtration.
Nearly all of the residual ester left on the APAP filter cake was then removed by
washing with the aqueous phase resulting from extraction of the oximation product
with ester. The following procedure was used for Examples 113-115.
[0085] The Beckmann reaction mixture was filtered under air, and the ethyl acetate filtrate
was transferred to a separatory funnel. The crude solid APAP filter cake, which still
contained about 35 g of ethyl acetate that could not be removed by filtration, was
slurried at about 25° C with the aqueous phase from extraction of the oximation reaction
mixture. The resulting aqueous APAP slurry was stirred at about 25° C while being
neutralized to about pH 6-6.5 by addition of 20 wt % aqueous sodium hydroxide (80-110
drops). The neutralized slurry was filtered to wash most of the ethyl acetate off
the crude neutralized solid APAP with the aqueous phase. The aqueous wash liquor filtrate,
which contained the ethyl acetate washed off the crude neutralized solid APAP, was
added to the ethyl acetate filtrate in the separatory funnel. The contents of the
separatory funnel were mixed well and then allowed to settle to extract the aqueous
wash liquor filtrate with the ethyl acetate filtrate. Such extraction permits transfer
of ethyl acetate and recyclable aromatics such as 4-HAP oxime from the aqueous wash
liquor filtrate to the ethyl acetate filtrate phase.
[0086] The aqueous phase was drained from the ethyl acetate phase in the separatory funnel
and was used to reslurry and wash the crude neutralized solid APAP. After filtration
of the resulting slurry, the aqueous wash liquor filtrate was remixed with the ethyl
acetate phase in the separatory funnel, and the resulting mixture was allowed to settle.
[0087] The procedure of the previous paragraph was repeated five more times. The resulting
aqueous phase is considered to be a waste stream in Table 12. The resulting ethyl
acetate filtrate phase was retained for recycle to the ethyl acetate phase from extraction
of the next batch's aqueous oximation product. The neutralized and washed solid APAP
was purified by known methods. Results are shown in Table 12.
[0088] In Examples 116-118, the acetaminophen product was at least partially neutralized
before filtration. Nearly all of the residual ester left on the APAP filter cake was
removed by washing with the aqueous phase resulting from extraction of the oximation
product with ester. The following procedure was used for Examples 116-118.
[0089] Aqueous NaOH (20 wt %; 40-70 drops) was added to a 30 mL aliquot of the aqueous phase
resulting from extraction of the crude oximation reaction mixture with ethyl acetate.
This aliquot was then mixed with the crude Beckmann reaction mixture by stirring for
about three minutes at about 25° C. The resulting mixture was filtered under air,
and the wet ethyl acetate filtrate was transferred to a separatory funnel. The partially
neutralized crude solid APAP filter cake, which still contained about 35 g of ethyl
acetate that could not be removed by filtration, was slurried at about 25° C with
the remainder of the aqueous phase from extraction of the crude oximation reaction
mixture. The resulting aqueous APAP slurry was filtered to wash most of the ethyl
acetate off the solid APAP with the aqueous phase. The aqueous wash liquor filtrate,
which contained the ethyl acetate washed off the solid APAP, was added to the wet
ethyl acetate filtrate in the separatory funnel. Additional 20 wt % aqueous sodium
hydroxide (20-30 drops) was also added to the separatory funnel. The contents of the
separatory funnel were mixed well and then allowed to settle to extract the aqueous
wash liquor filtrate with the ethyl acetate filtrate. Such extraction permits transfer
of ethyl acetate and recyclable aromatics such as 4-HAP oxime from the aqueous wash
liquor filtrate to the ethyl acetate filtrate phase.
[0090] The aqueous phase (pH of about 5.5-6.0) was drained from the ethyl acetate phase
in the separatory funnel and was used to reslurry and was the crude neutralized solid
APAP. After filtration of the resulting slurry, the aqueous wash liquor filtrate was
remixed with the ethyl acetate phase in the separatory funnel, and the resulting mixture
was allowed to settle.
[0091] The procedure of the previous paragraph was repeated four more times. The resulting
aqueous phase is considered to be a waste stream in Table 12. The resulting ethyl
acetate filtrate phase was retained for recycle to the ethyl acetate phase from extraction
of the next batch's aqueous oximation product. The neutralized and washed solid APAP
was purified by known methods. Results are shown in Table 12.
EXAMPLES 119-121
[0092] In Examples 119-121, oximation and Beckmann reactions were integrated with n-butyl
acetate. The crude solid APAP product was filtered, washed with n-butyl acetate, neutralized
in water, and then freed from residual n-butyl acetate by water-assisted distillation.
In the following procedure for Examples 119-121, figures in parenthetical triplets
correspond to Example 119, Example 120, and Example 121, respectively.
[0093] To a stirred mixture of 4-HAP (1360 g), hydroxylamine sulfate (865 g), and water
(2596 mL) heated to 80° C was added a solution of sodium hydroxide (414.8 g) in water
(1659 mL) over about one minute. The resulting stirred mixture was then heated to
about 100° C for about 45 minutes before adding n-butyl acetate (4.0 L, 4.5 L, 4.0
L) consisting of the wash liquor (2.2 L, 2.0 L, 2.1 L) from the n-butyl acetate wash
of the previous batch's crude solid APAP product, the second n-butyl acetate extract
(1603.6 g, 1709 g, 1729.5 g) of the aqueous phase from the previous batch's oximation
reaction, and the n-butyl acetate phase (0 mL, 600 mL, 0 mL) of the azeotrope distilled
off the hot aqueous solution of APAP product from the previous batch. After having
been stirred for about five minutes, the hot, solid-free mixture of n-butyl acetate
and aqueous oximation products was allowed to separate into two liquid phases over
about three minutes. The hot, solid-free aqueous phase was drained from a hot, solid-free
solution of 4-HAP oxime in n-butyl acetate. Fresh make-up n-butyl acetate (909 g,
0 g, 0 g) and the n-butyl acetate phase (590 mL, 0 mL, 0 mL) of the azeotrope distilled
off the hot aqueous solution of APAP product from the previous batch were then added
to the solution of 4-HAP oxime in n-butyl acetate.
[0094] The 4-HAP oxime/n-butyl acetate solution was dried by azeotropic distillation as
follows. The 4-HAP oxime/n-butyl acetate solution was stirred and refluxed under nitrogen
at about 62-74° C and about 71-112 mm HgA pressure while about 425-433 g of aqueous
phase was removed from the reflux condensate with a Dean-Stark trap. After addition
of activated carbon (13.6 g, 27.2 g, 27.2 g), the n-butyl acetate filtrate (2240 g,
3000 g, 3360 g) from the previous batch's Beckmann reaction mixture, and fresh make-up
n-butyl acetate (0 g, 612 g, 0 g), azeotropic drying of the stirred 4-HAP oxime/n-butyl
acetate solution was continued by refluxing the solution at about 70-74° C and about
73-97 mm HgA pressure for about half an hour while additional aqueous phase was removed
from the reflux condensate with the Dean-Stark trap. The 4-HAP oxime/n-butyl acetate
solution was then recirculated through a filter at about 65-72° C to remove activated
carbon. After addition of KI (2.72 g), azeotropic drying of the stirred 4-HAP oxime/n-butyl
acetate solution was continued with the Dean-Stark trap at about 70-74° C and about
73-97 mm HgA pressure until the reflux condensate was substantially free of a separate
aqueous phase. The total amount of aqueous phase removed by the Dean-Stark trap was
450-463 g. Azeotropic drying of the stirred 4-HAP oxime/n-butyl acetate solution was
then completed by simple distillation at 72-73° C. While about 4 L of n-butyl acetate
distillate was collected, the distillation pressure was reduced from about 92 mm HgA
to about 72 mm HgA. The resulting undistilled residue was a substantially dry 4-HAP
oxime/n-butyl acetate mixture.
[0095] The aqueous phase from extraction of the aqueous oximation products with n-butyl
acetate was extracted again, this time at about 25° C with about 2 L of the n-butyl
acetate distillate from the azeotropic drying step. The resulting n-butyl acetate
extract (1709 g, 1729.5 g, 1710.7 g) was saved for recycle to the 4-HAP oxime extraction
step of the next batch. The resulting aqueous phase is considered to be a waste stream
in Table 13.
[0096] A solid Vilsmeier reagent was prepared by stirring DMF (32 mL) and thionyl chloride
(16 mL) in n-butyl acetate (250 mL) at about 23° C under nitrogen for about 20 minutes.
The n-butyl acetate suspension of the solid Vilsmeier reagent was then added as the
Beckmann reaction catalyst in about 13-16 portions over about 64-69 minutes to the
4-HAP oxime/n-butyl acetate mixture dried by azeotropic distillation. During the catalyst
addition, the Beckmann reaction mixture was stirred under air-free conditions at a
temperature of about 42-52° C maintained by n-butyl acetate reflux at about 18 torr
absolute pressure. After all catalyst had been added, the stirred Beckmann reaction
mixture was allowed to cool to 31-33° C over 16-23 minutes before being chilled to
10° C.
[0097] The Beckmann reaction mixture was then filtered, and the resulting n-butyl acetate
filtrate (3000 g, 3371 g, 3058 g) was saved for recycle to the azeotropic drying step
of the next batch. The crude solid APAP product filtered off the Beckmann reaction
mixture was washed at about 25° C with about 2 L of the n-butyl acetate distillate
from the azeotropic drying step. The n-butyl acetate wash liquor, which contained
dissolved recyclable aromatics including unreacted 4-HAP oxime, was filtered off the
crude solid APAP product and saved for recycle to the 4-HAP oxime extraction step
of the next batch.
[0098] The crude solid APAP filter cake, which still contained about 400 mL of n-butyl acetate
that could not be removed by filtration, was slurried in about 6 L of water. The resulting
aqueous APAP slurry was stirred at about 25° C while being neutralized to about pH
6-6.5 by addition of 5 wt % aqueous sodium hydroxide (100 g, 100 g, 160 g). The neutralized
aqueous APAP slurry was stirred and heated to about 100° C under nitrogen to dissolve
the solid APAP. The resulting solution was then distilled with stirring at about 97-104°
C and about 0-3 psig pressure to remove an azeotrope distillate consisting of an upper
n-butyl acetate phase (600 mL, 348 mL, 315 mL) and a lower aqueous phase (250 mL,
222 mL, 265 mL). The n-butyl acetate phase was separated from the aqueous phase and
was recycled to the 4-HAP oxime extraction step of a subsequent batch. The resulting
undistilled residue was then chilled to about 10° C to recrystallize the dissolved
APAP. The recrystallized APAP was filtered and further purified by known methods.
Results are shown in Table 13.
EXAMPLE 122
[0099] In this example, 4-HAP oxime was converted to recrystallized APAP in a single vessel
without filtration of the ester Beckmann reaction mixture. After addition of water,
the last portion of ester solvent was removed by water-assisted distillation.
[0100] The catalyst mixture for the Beckmann rearrangement was prepared as follows. Acetonitrile
(5 mL) was added to solid trimethyloxonium tetrafluoroborate (5.14 g), and the resulting
mixture was stirred at about 25° C under nitrogen for 30 minutes before more acetonitrile
(4 mL) was added. All solids dissolved while the resulting mixture was stirred at
about 25° C under nitrogen for an additional 30 minutes. Stirring was then discontinued,
and colorless crystals precipitated while the mixture stood under nitrogen at about
25° C for about 24 hours. All excess acetonitrile was then evaporated from the mixture
under vacuum at 0-25° C. The resulting colorless crystalline residue, which is known
to be about 4.96 g of N-methylaceto-nitrilium tetrafluoroborate from S. C. Eyley,
R. G. Giles, and H. Heaney, Tetrahedron Letters, Vol. 26. No. 38, p. 4649, 1985, was
resuspended in n-butyl acetate (30 mL) under nitrogen to provide the catalyst mixture
for the Beckmann rearrangement.
[0101] The n-butyl acetate suspension of N-methylacetonitrilium tetrafluoroborate was then
added as the Beckmann reaction catalyst in about 15 portions over about 80 minutes
to a stirred suspension of 4-HAP oxime (200.0 g) in n-butyl acetate (about 430 mL).
During the catalyst addition, the Beckmann reaction mixture was stirred under air-free
conditions at a temperature of about 48° C maintained by n-butyl acetate reflux at
about 30 mm HgA pressure. An additional 30 mL of n-butyl acetate was added to the
last portions of solid catalyst to assist suspension and addition to the Beckmann
reaction mixture. The stirred reaction mixture was allowed to cool to 30° C, and about
275 mL of the n-butyl acetate solvent was distilled off the stirred Beckmann reaction
mixture at about 30° C and 3 mm HgA pressure.
[0102] Water (1.0 L) was added to the remaining n-butyl acetate slurry of Beckmann reaction
products, and the resulting mixture was stirred at about 25° C while being neutralized
to about pH 6 by addition of 25 wt% aqueous sodium hydroxide (10 g) followed by concentrated
aqueous HCl (70 drops). Substantially all n-butyl acetate was then removed from the
stirred neutralized Beckmann reaction products by distillation as a water azeotrope
at about 24° C and about 10-20 mm HgA pressure. The resulting distillation residue
was then stirred and heated to about 83° C under 1 atm of nitrogen to completely dissolve
the solid Beckmann reaction products. The resulting stirred aqueous solution precipitated
recrystallized APAP on chilling to 5° C. The recrystallized APAP was filtered from
the aqueous mother liquor, washed with water (5° C, 200 mL), and then dried at about
0.05 mm HgA pressure to provide the purified APAP. Results are shown in Table 13.
EXAMPLE 123
[0103] The APAP synthesis of Example 122 was repeated with N-isopropylacetonitrilium tetrachloroferrate
as the Beckmann rearrangement catalyst instead of N-methylacetonitrilium tetrafluoroborate.
[0104] The catalyst mixture for the Beckmann rearrangement was prepared under nitrogen with
magnetic stirring and ice bath cooling as follows. A mixture of anhydrous ferric chloride
(8.10 g) and isopropyl chloride (35 mL) was stirred under nitrogen for 30 minutes
while being chilled in an ice bath. While continuing ice bath cooling and stirring
under nitrogen, acetonitrile (2.65 mL) was then added dropwise over ten minutes. The
resulting red-orange suspension was then stirred under nitrogen with ice bath cooling
for 16 hours before the excess isopropyl chloride was evaporated under vacuum at 0-25°
C. The resulting brownish-yellow solid residue, which is known to be about 14.07 g
of N-isopropylacetonitrilium tetrachloroferrate from R. Fuks, Tetrahedron, Vol. 29
(1973), p. 2150, was resuspended in n-butyl acetate (30 mL) under nitrogen and used
promptly as the catalyst mixture for the Beckmann rearrangement.
[0105] The n-butyl acetate suspension of N-isopropylaceto-nitrilium tetrachloroferrate was
then added as the Beckmann reaction catalyst in about 15 portions over about 57 minutes
to a stirred suspension of 4-HAP oxime (200.0 g) in n-butyl acetate (about 450 mL).
During the catalyst addition, the Beckmann reaction mixture was stirred under air-free
conditions at a temperature of about 43-50° C maintained by n-butyl acetate reflux
at about 25 mm HgA pressure. About 275 mL of the n-butyl acetate solvent was then
distilled off the stirred Beckmann reaction mixture at about 30° C and 10 mm HgA pressure.
[0106] Water (1.0 L) was added to the remaining n-butyl acetate slurry of Beckmann reaction
products, and the resulting mixture was stirred at about 25° C while being neutralized
to about pH 6.5 by addition of 25 wt% aqueous sodium hydroxide (23.1 g). Substantially
all n-butyl acetate was then removed from the stirred neutralized Beckmann reaction
products by distillation as a water azeotrope at about 29° C, 54 mm HgA pressure to
36° C, 36 mm Hg pressure. The resulting distillation residue was then stirred and
heated to about 90° C under 1 atm of nitrogen to completely dissolve the solid Beckmann
reaction products. The resulting stirred aqueous solution precipitated recrystallized
APAP on chilling to 3° C. The recrystallized APAP was filtered from the aqueous mother
liquor, washed with water (200 mL), and then dried at about 0.05 mm HgA pressure to
provide the purified APAP. Results are shown in Table 13.
EXAMPLE 124
[0107] In this example, 4-HAP is converted to recrystallized APAP in a single vessel without
filtration of the ester Beckmann reaction mixture. After addition of water, the last
portion of ester solvent is removed by steam-assisted distillation.
[0108] To a stirred mixture of 4-HAP (200 g), hydroxylamine sulfate (127.2 g), and water
(382 mL) heated to 80° C is added a solution of sodium hydroxide (61 g) in water (244
mL) over about one minute. The resulting stirred mixture is then heated to about 100°
C for about 45 minutes before adding n-butyl acetate (about 720 mL). After being stirring
for about five minutes, the hot, solid-free mixture of n-butyl acetate and aqueous
oximation products is allowed to separate into two liquid phases over about three
minutes. The hot, solid-free aqueous phase is drained from a hot, solid-free solution
of 4-HAP oxime in n-butyl acetate.
[0109] More n-butyl acetate (480 mL) is added to the 4-HAP oxime/n-butyl acetate solution,
and the resulting mixture is dried by azeotropic distillation as follows. The 4-HAP
oxime/n-butyl acetate mixture is stirred and refluxed under nitrogen at about 55-65°
C and about 80 mm HgA pressure while about 50 g of aqueous phase is removed from the
reflux condensate with a Dean-Stark trap and until the reflux condensate is substantially
free of a separate aqueous phase. Azeotropic drying of the stirred 4-HAP oxime/n-butyl
acetate mixture is then completed by simple distillation at about 80 mm HgA pressure.
While about 720 mL of n-butyl acetate distillate is collected, the temperature of
the undistilled residue rises from about 65° C to about 75° C. Potassium iodide (about
0.4 g) is then added to the resulting undistilled residue, which is a substantially
dry mixture of 4-HAP oxime in n-butyl acetate.
[0110] A suspension of N-methylacetonitrilium tetrafluoroborate (5.5 g) in n-butyl acetate
(about 50 mL) is then added as the Beckmann reaction catalyst in about 15 portions
over about 80 minutes to the dry mixture of 4-HAP oxime in n-butyl acetate. During
the catalyst addition, the Beckmann reaction mixture is stirred under air-free conditions
at a temperature of about 48° C maintained by n-butyl acetate reflux at about 30 mm
HgA pressure. The stirred Beckmann reaction mixture is then cooled to about 25° C
before addition of water (about 500 mL). The resulting mixture is stirred at about
25° C while being neutralized to about pH 6 by addition of 25 wt% aqueous sodium hydroxide.
Water vapor (i.e., steam) is then passed into the stirred slurry of neutralized Beckmann
reaction products to remove substantially all n-butyl acetate by distillation as a
water azeotrope at about 24° C and about 10-20 mm HgA pressure. Water is added to
the resulting aqueous slurry of neutralized Beckmann reaction products as necessary
to increase the slurry's water content to about 1.0 L. The APAP product is then recrystallized
and recovered as described in Example 122. All n-butyl acetate distillates are recycled
to the next batch.
EXAMPLE 125
[0111] The APAP synthesis of Example 124 is repeated with the following modifications. Activated
carbon (2.00 g) is added to the mixture of 4-HAP oxime and n-butyl acetate after azeotropic
distillation with the Dean-Stark trap and before distillative removal of the 720 mL
of n-butyl acetate distillate. Prior to recrystallization of the APAP product, the
hot aqueous solution of Beckmann reaction products is recirculated through a filter
to remove the activated carbon.
[0112] The following Tables 1-13 use the following abbreviations:
- Ac
- the acetyl radical CH₃C=O
- acct
- accountability
- APAP
- N-acetyl-p-aminophenol (acetaminophen)
- ArSO₃Na
- sodium 4-hydroxybenzenesulfonate
- conv
- conversion
- CTMAB
- cetyltrimethyl ammonium bromide
- DMA
- N,N-dimethylacetamide
- DMF
- N,N-dimethylformamide
- Et
- the ethyl radical CH₃CH₂
- 4-HAP
- 4-hydroxyacetophenone
- HPLC
- high pressure (performance) liquid chromatography
- limit of color
- the 420 nm absorbance of the supernate obtained from centrifugation of a slurry of
10 g of solid sample in 10 mL of methanol
- MHBA
- N-methyl-p-hydroxybenzamide
- MSA
- methanesulfonic acid
- NMP
- N-methylpyrrolidinone
- others
- all HPLC-detectable aromatics not specifically listed
- oxime
- 4-hydroxyacetophenone oxime
- Oxime-O-SO₃K
- potassium 4-hydroxyacetophenone oxime-O-sulfonate
- Ph
- the phenyl radical C₆H₅
- PPA
- polyphosphoric acid
- ppm
- parts per million by weight
- SDS
- sodium dodecyl sulfate
- SO₃·Pyr
- sulfur trioxide-pyridine complex
- temp
- temperature
- p-TSA
- p-toluenesulfonic acid
- wt
- weight
[0113] Names of some reagents shown in Tables 1-13 are indicated below:
- SOCl₂
- thionyl chloride
- CH₃SO₂Cl
- methanesulfonyl chloride
- CF₃SO₂Cl
- trifluoromethanesulfonyl chloride
- CF₃SO₃H
- trifluoromethanesulfonic acid
- MSA Anhydride
- methanesulfonic anhydride
- p-TSA Anhydride
- p-toluenesulfonic anhydride
- ClSO₃H
- chlorosulfonic acid
- P₂O₅
- phosphorus pentoxide
- (CH₃O)₂SO
- dimethyl sulfite
- POCl₃
- phosphorus oxytrichloride
- PhPOCl₂
- phenylphosphonic dichloride
- Ph₂POCl
- diphenylphosphinic chloride
- Et₂O·BF₃
- boron trifluoride etherate
- ((AcO)₂B)₂O
- tetraacetyl diborate
- CH₃CN⁺CH₃BF₄⁻
- N-methylacetonitrilium tetrafluoroborate
- CCl₃CO₂H
- trichloroacetic acid
- CCl₃COCl
- trichloroacetyl chloride
- (CCl₃CO)₂O
- trichloroacetic anhydride
- CF₃CO₂H
- trifluoroacetic acid
- (CF₃CO)₂O
- trifluoroacetic anhydride
- NEt₃
- triethylamine
- CCl₃CO₂SO₂CH₃
- Mixed anhydride of trichloroacetic and methanesulfonic acids
- ClCO₂CH₃
- methyl chloroformate
- ClCON(CH₃)₂
- N,N-dimethylcarbamyl chloride
- CH₃NCO
- methyl isocyanate
- ClCO₂CCl₃
- trichloromethyl chloroformate (diphosgene)
- ClCOCO₂Et
- ethyl oxalyl chloride
- ClCOCOCl
- oxalyl chloride
- CF₃CO₂Na
- sodium trifluoroacetate
- CH₃CO₂Na
- sodium acetate
- (NH₄)⁺ (H₂PO₄)⁻
- ammonium dihydrogen phosphate
- Na₂S₂O₅
- sodium metabisulfite
- B(OCH₃)₃
- trimethyl borate
[0114] In the following Tables 1-13, "accountability" is 100% times the sum total moles
of all HPLC-detectable aromatics in all recovered outputs divided by the sum total
moles of all aromatics in all feeds. If an aromatic's "net make" is the total moles
of that aromatic in all recovered outputs minus the total moles of that aromatic in
all feeds, then that aromatic's "efficiency" is 100% times that aromatic's net make
divided by the sum total net makes of all HPLC-detectable aromatics with a positive
net make. The unconverted fraction of oxime is the total moles of all oxime in all
recovered outputs divided by the total moles of all oxime in all feeds. The normalized
unconverted fraction of oxime is 100 times the unconverted fraction of oxime divided
by the accountability defined above. "Conversion" is 100% times the difference of
1.0 and the normalized unconverted fraction of oxime. In all of these calculations,
all 4-HAP fed to an oximation reaction is considered to be oxime feed and not 4-HAP
feed.
[0115] In Tables 12 and 13, "unrecycled output" consists of the purified APAP and the "waste
streams." For Examples 122 and 123 in Table 13, the "waste streams" consist of the
aqueous mother and wash liquors from the APAP recrystallization. For Examples 119-121
in Table 13, the "waste streams" consist of the aqueous mother and wash liquors from
the APAP recrystallization and the aqueous phase resulting from the second extraction
of the oximation reaction mixture with butyl acetate. For Examples 113-118 in Table
12, the "waste streams" consist of the aqueous mother and wash liquors from an APAP
recrystallization and the aqueous phase resulting from extraction of the oximation
reaction mixture and subsequent neutralization and washing of the crude solid APAP
product. All other aromatic-containing output from Examples 113-121 was recycled to
the next batch. All aromatic-containing output from Examples 122 and 123 was the above-described
unrecycled output.
[0116] None of the figures in Tables 1-13 include mechanical losses or losses to activated
carbon/Celite filter cakes. It is believed that such losses account for substantially
all aromatic products not represented in Tables 1, 12, and 13. It is therefore further
believed that with minimization of such losses in commercial scale production, actual
APAP yields would closely approach the figures shown in Tables 12-13 for "Purified
APAP" "As a Molar Percentage of all Unrecycled Output."
[0117] In the following claims, "filtering" and "filtration" are to be interpreted as generic
terms fully embracing the actions and concepts of centrifuging and centrifugation.
1. A process for production of N-acetyl-para-aminophenol from 4-hydroxyacetophenone oxime
comprising adding a Beckmann rearrangement catalyst to said 4-hydroxyacetophenone
oxime to form said N-acetyl-para-aminophenol product, said catalyst having an electrophilic
carbon atom at which said catalyst reacts with said oxime.
2. The process of claim 1, wherein said Beckmann rearrangement catalyst comprises a nitrilium
cation.
3. The process of claim 2, wherein said nitrilium cation is N-methylacetonitrilium cation.
4. The process of claim 2, wherein said Beckmann rearrangement catalyst further comprises
tetrafluoroborate anion.
5. The process of claim 4, wherein said Beckmann rearrangement catalyst is N-methylacetonitrilium
tetrafluoroborate.
6. The process of claim 1, wherein said Beckmann rearrangement catalyst is a trihaloacetic
anhydride.
7. The process of claim 1, wherein said Beckmann rearrangement catalyst is a vilsmeier
reagent prepared from a carboxylic acid amide.
8. The process of claim 7, wherein said amide is N,N-dimethylformamide.
9. The process of claim 1 wherein the Beckmann rearrangement is conducted in an alkyl
alkanoate solvent.
10. The process of claim 9, wherein the amount of said Beckmann rearrangement catalyst
is selected to achieve a conversion of said 4-hydroxyacetophenone oxime in the range
of 50% to 95% to lessen formation of N-methyl-p-hydroxybenzamide.
11. The process of claim 9, wherein said 4-hydroxyacetophenone oxime is reacted in the
presence of a base to lessen formation of N-methyl-p-hydroxybenzamide.
12. The process of claim 11 wherein said base is a metabisulfite salt.
13. The process of claim 11 wherein said base is a salt of a carboxylic acid.
14. The process of claim 11 wherein said base is a tertiary amine.
15. The process of claim 11 wherein said base is a phosphate salt.
16. A process for production of N-acetyl-para-aminophenol from 4-hydroxyacetophenone oxime
comprising contacting a mixture of an alkyl alkanoate solvent and said 4-hydroxyacetophenone
oxime with an amount of a Beckmann rearrangement catalyst selected to achieve a conversion
of said 4-hydroxyacetophenone oxime to said N-acetyl-para-aminophenol in the range
of about 50% to about 95% to reduce formation of N-methyl-p-hydroxybenzamide.
17. A process for production of N-acetyl-para-aminophenol from 4-hydroxyacetophenone oxime
comprising contacting a mixture of an alkyl alkanoate solvent and said 4-hydroxyacetophenone
oxime with activated carbon to remove colored impurities and contacting said mixture
with a Beckmann rearrangement catalyst to produce said N-acetyl-para-aminophenol.
18. The process of claim 17 wherein said activated carbon is removed prior to contacting
said mixture with the Beckmann rearrangement catalyst.
19. A process for production of N-acetyl-para-aminophenol from 4-hydroxyacetophenone oxime
comprising contacting a mixture of said 4-hydroxyacetophenone oxime and a substantially
water-immiscible solvent with a Beckmann rearrangement catalyst to form a mixture
of said N-acetyl-para-aminophenol and said solvent, adding water to said mixture and
forming a product mixture of said N-acetyl-para-aminophenol, said water and said substantially
water-immiscible solvent, and subsequently removing substantially all of said substantially
water-immiscible solvent from said product mixture.
20. The process of claim 19 wherein said product mixture comprises solid N-acetyl-para-aminophenol.
21. The process of claim 20, wherein said product mixture comprising said solid N-acetyl-para-aminophenol
is formed by removing a portion of said solvent by filtration subsequent to the Beckmann
rearrangement.
22. The process of claim 21 further comprising: washing said solid N-acetyl-para-aminophenol
with said substantially water-immiscible solvent before said removal of substantially
all of said substantially water-immiscible solvent and recovering from said washing
a wash liquor of recyclable aromatics in said substantially water-immiscible solvent.
23. The process of claim 21, wherein said removal of substantially all of said substantially
water-immiscible solvent from said product mixture comprising said solid N-acetyl-para-aminophenol
is achieved by washing said product mixture with an aqueous medium.
24. The process of claim 23 further comprising recovering an aqueous wash liquor from
said washing of said product mixture and extracting said aqueous wash liquor with
said substantially water-immiscible solvent to obtain a solution of recyclable aromatics
in said substantially water-immiscible solvent.
25. The process of claim 24 wherein said aqueous wash liquor is extracted with a portion
of said substantially water-immiscible solvent removed by filtration subsequent to
the Beckmann rearrangement.
26. The process of claim 19, wherein said removal of said substantially water-immiscible
solvent from said product mixture is achieved by distillation.
27. The process of claim 26, wherein substantially all of said substantially water-immiscible
solvent is removed from said product mixture by distillation.
28. The process of claim 26, wherein said distillation is carried out by passing water
vapor into said product mixture.
29. The process of claim 26 wherein said product mixture comprises solid N-acetyl-para-aminophenol.
30. The process of claim 29, wherein said product mixture comprising said solid N-acetyl-para-aminophenol
is formed by removing a portion of said solvent by filtration subsequent to Beckmann
rearrangement.
31. A process for production of N-acetyl-para-aminophenol from 4-hydroxyacetophenone comprising
reacting said 4-hydroxyacetophenone with hydroxylamine in the presence of water to
form 4-hydroxyacetophenone oxime, extracting said oxime with a substantially water-immiscible
solvent to form an aqueous first mixture and a second mixture of said oxime in said
substantially water-immiscible solvent, contacting said second mixture with a Beckmann
rearrangement catalyst to form a third mixture of said N-acetyl-para-aminophenol and
said solvent, adding water to said third mixture and forming a product mixture of
said N-acetyl-para-aminophenol, said water and said water-immiscible solvent, and
subsequently removing substantially all of said substantially water-immiscible solvent
from said product mixture.
32. The process of claim 31 wherein said product mixture comprises solid N-acetyl-para-aminophenol
and wherein said removal of substantially all of said substantially water-immiscible
solvent from said product mixture is achieved by washing said product mixture comprising
said solid N-acetyl-para-aminophenol with an aqueous medium.
33. The process of claim 32, wherein said aqueous medium comprises at least a portion
of said first mixture.
34. The process of claim 32 further comprising recovering an aqueous wash liquor from
said washing of said product mixture and extracting said aqueous wash liquor with
said substantially water-immiscible solvent to obtain a solution of recyclable aromatics
in said substantially water-immiscible solvent.
35. The process of claim 32 further comprising extracting said first mixture with a portion
of said substantially water-immiscible solvent removed by filtration subsequent to
Beckmann rearrangement.